HIV-1 drug-resistance is a growing public health problem. Acquired Immunodeficiency Syndrome (AIDS) and its related disorders, caused by retrovirus Human Immunodeficiency Virus Type 1 (HIV-1), are responsible for more than a million deaths each year. Much of this mortality is due to the rise of drug-resistant mutant virus. Current treatment of HIV-1 infection mainly consists of the use of combinations of HIV-1 reverse transcriptase and protease enzyme inhibitors. However, numerous side effects and rapid emergence of drug resistant variants greatly limit their use in many AIDS patients. Therefore, it is important to develop drugs targeting alternative steps in viral replication cycle. Among the new approaches, the inhibition of integrase (the third viral enzyme) has proved to be an important target. The long-term goal of this research proposal is to help in the design and development of potent and mechanistically novel HIV-1 integrase inhibitors. Our recent studies on HIV-1 protease inhibitors have established that the hybrid QSAR approach using the artificial neural network (ANN) and multiple linear regression (MLR) based QSAR models can provide much better predictability as well as mechanistic interpretation for modeling drug-receptor interactions. We now propose to conduct an in-depth QSAR study on HIV-1 integrase inhibitors using this hybrid approach. The specific aims of the proposed research are development of hybrid QSAR approach (Aim 3) using the ANN and MLR models developed in Aims 1 &2. The results of QSAR studies will be supported by molecular modeling studies (Aim 4). These studies would provide a much better understanding of the interaction(s) between HIV-1 integrase and its inhibitors, and enable the design of new therapeutic strategies. The results of this study would help in lead exploitation, in decreasing the number of chemicals finally subjected to costly assays and animal testing, and in designing experiments to test the biological activity in vitro and in vivo. PUBLIC HEALTH RELEVANCE: Project Narrative HIV-1 drug-resistance is a growing public health problem. AIDS and its related disorders, caused by HIV-1, are responsible for more than a million deaths each year. Much of this mortality is due to the rise of drug-resistant mutant virus. The goal of this project is to understand the interactions between the HIV-1 integrase enzyme and its inhibitors that will help in the design of new drugs active against drug-resistant HIV-1.